Environmental Factor, April 2011, National Institute of Environmental Health Sciences

Microglia: A complex resident immune cell of the brain

By Emily ZhouApril 2011

Harry's hypothesis challenges longstanding conventional wisdom about microglia, which she says can actually change function in response to different kinds of injury, environmental exposure, and disease.
(Photo courtesy of Steve McCaw)

Levin is a gracious host who often takes advantage of talent from nearby universities, NIEHS, and the U.S. Environmental Protection Agency for the weekly ITEH Lecture Series presentations.
(Photo courtesy of Steve McCaw)

Annette Kirshner, Ph.D., a health scientist administrator in the Cellular, Organs and Systems Pathobiology Branch of the NIEHS Division of Extramural Research Training, made the trip to Durham for Harry's seminar.
(Photo courtesy of Steve McCaw)

NIEHS Principal Investigator Jean Harry, Ph.D.(http://www.niehs.nih.gov/research/atniehs/labs/ntp/nt/index.cfm), introduced the complex processes of neuroinflammation in the brain during a talk March 4 before an audience of students and faculty gathered at the Duke University.

Harry is head of the Neurotoxicology Group in the NIEHS Laboratory of Toxicology and Pharmacology. She stressed the importance of understanding the different patterns of activation of microglia as a defense mechanism against disease processes in the brain, such as inflammation, trauma, ischemia, tumor, neurodegeneration, and neurotoxicity.

"The take-home message [of her seminar]," said Harry, "is that morphological phenotypes of microglia can contribute to the identification and understanding of multiple and shifting roles of microglia from neurotoxicity to neuroprotection." She also emphasized, "Targeting of therapeutic interventions requires an understanding of all interdependent processes of neuroinflammation and microglial function."

Neuroinflammation is a highly complex process associated with different cellular mechanisms and often involving tumor necrosis factor alpha. A critical component lies in discriminating between the contribution of resident microglia, the immune cells of the brain, and the contribution of the infiltrating macrophage associated with compromise to the blood-brain barrier.

Referring to an immunofluorescence image of a brain stained for various cellular markers after trauma, Harry pointed out the problem: "As they express the same markers and morphology, are we looking at [neuroinflammatory] responses from the resident microglia of the brain or are we looking at responses from brain macrophages derived from infiltrating peripheral monocytes from the blood?" She cautioned, "Within any disease state or experimental model, multiple cellular processes are occurring at any one time." According to Harry, it's imperative that multiple markers both for inflammation and for other cellular events be examined to interpret the impact of such changes.

Microglia: Morphology, activation, and function

Microglia are resident cells of the central nervous system (CNS) that play an important role in removal of cellular debris and aberrant proteins. They serve to repair vascular damage, contribute to synaptic stripping and remodeling during development, directly communicate with neurons, provide growth factors, and change expression of antioxidant proteins in astrocytes for protection. "It's very possible," said Harry, "that dysregulation of microglial functions contributes to chronic neuroinflammation, but also [results] in a deficit in repair response."

"The resident immune network of the brain coordinates a diverse array of intraneural protective host responses, as well as pathogenic responses to regulate complex processes of initiation, propagation, and suppression of immune and inflammatory responses," Harry explained.

This process is normally tightly regulated, she continued, "[but] under pathological states, the immune responses are spatially and temporally dysregulated, leading to detrimental consequences." In such cases, simple down-regulation of these signals and microglia does not provide neuroprotection, but rather exacerbates the injury, suggesting an alternate neuroprotective role of microglia.

Ongoing research in Harry's laboratory examines an in vivo model of brain injury to identify resident microglia heterogeneity and the presence of cellular markers, to characterize the neuroinflammatory response and the shift in microglia to a neuroprotective phenotype. When activated, microglia undergo morphological changes from a ramified morphology, to a retraction of processes, and finally to a rounded, ameboid shape. Harry presented data supporting the hypothesis that these changes correspond with functional changes of the microglia and suggested that a closer examination of this heterogeneity of microglia in injury and remodeling will assist researchers in understanding the multiple contributions of these cells and provide insight into therapeutic intervention.

Harry's talk was part of the Duke Integrated Toxicology and Environmental Health(http://toxicology.geneimprint.com/) (ITEH) Program seminar series. Edward Levin, Ph.D.(http://toxicology.geneimprint.com/people/index.php?name=Levin.E), who hosted Harry, is a professor of psychiatry and psychological and brain sciences at Duke. ITEH is supported in part by the NIEHS Superfund.

(Emily Zhou, Ph.D., is a research fellow in the NIEHS Laboratory of Signal Transduction Inositol Signaling Group.)

Cascade of responses in neuroinflammation

Just like any inflammation, when neuroinflammatory response is initiated, it is characterized by an induction of a pro-inflammatory response and classical macrophage activation. It is then followed by expression of anti-inflammatory cytokines and the initiation of negative feedback pathways to down-regulate pro-inflammatory signaling pathways. The overall result is repair, resolution, and return to tissue homeostasis. Chronic inflammation, however, undermines these checks and balances to control the innate immune response and may result in recruitment of peripheral immune cells for assistance. This can lead to a concurrent expression of pro-inflammatory cytokines and those associated with repair, which will make it difficult to identify target sites for therapeutic regulation.

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